Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
  • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to 2,3-indoldione derivatives.
• it relates to 2,3-indoldione derivatives, a process for their preparation, pharmaceutical preparations containing these derivatives and the use of these derivatives.
• the 2,3-indoldione derivatives according to the invention are compounds of the general formula wherein R is isopropyl or t-butyl, R is hydrogen or lower alkyl and R 2 is lower alkyl or lower aralkyl, and pharmaceutically acceptable acid addition salts thereof.
• lower alkyl as used in the present specification uses straight-chain or branched alkyl groups which preferably contain 1 to 6 carbon atoms (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl , etc.).
• lower aralkyl as used in the present specification means a lower alkyl group as defined above, in which a hydrogen atom is substituted by an aryl group. Examples of such lower aralkyl groups are benzyl, ⁇ -phenethyl, etc.
• a preferred class of 2,3-indoldione derivatives in accordance with the present invention, comprises compounds of formula I, wherein R is hydrogen and R 2 is lower alkyl, and pharmaceutically acceptable acid addition salts thereof.
• the reaction of a compound of formula II with an amine of formula III can be carried out in a manner known per se.
• the reaction can be carried out in the presence of an inert organic solvent. If an inert organic solvent is used, lower alkanols, such as methanol or ethanol, are suitable. On the other hand, it is also possible to use an excess of amine of the formula III, so that this also serves as a solvent.
• the reaction is advantageously carried out in a temperature range from about 0 ° C. to room temperature, preferably at room temperature and atmospheric pressure.
• the compounds of the formula I have an asymmetrically substituted carbon atom and can therefore occur in racemic or optically active forms.
• the present invention encompasses both the racemates and the optically active forms. If desired, a racemate can be separated into the optical isomers by methods known per se; for example by fractional crystallization of salts obtained with optically active acids.
• the compounds of formula I can be prepared by treatment with a pharmaceutically acceptable inorganic acid (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, etc.) or with a pharmaceutically acceptable organic acid (e.g. acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, methanesulfonic acid). p-toluenesulfonic acid, etc.) are converted into pharmaceutically acceptable acid addition salts.
• a pharmaceutically acceptable inorganic acid e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, etc.
• a pharmaceutically acceptable organic acid e.g. acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, methanesulfonic acid.
• p-toluenesulfonic acid, etc. are converted into pharmaceutically acceptable acid addition salts.
• a compound of the formula IV a compound known per se or a compound which can easily be prepared in a manner known per se is converted into a compound of the formula V.
• This conversion is carried out by reacting a compound of formula IV with oxalyl chloride in an inert organic solvent, preferably in an aromatic hydrocarbon, such as benzene, in a temperature range from about 50 ° C to 80 ° C and the reaction product obtained in a high-boiling inert organic solvents, preferably in a nitrated aromatic hydrocarbon, such as nitrobenzene, nitrotoluene, etc., heated to a temperature above about 160 ° C.
• an aromatic hydrocarbon such as benzene
• the lower alkoxy group -OR 5 in a compound of formula V is converted into the hydroxy group in a manner known per se; for example with boron tribromide at low temperatures (e.g. at about -70 ° C), pyridine hydrochloride at high temperatures (e.g. at about 200 ° C), etc. It should be noted that if R 2 is lower aralkyl, a method must be used which does not affect this group.
• a phenol of formula VI is reacted with an epichlorohydrin or epibromohydrin, preferably epichlorohydrin, in a manner known per se.
• the reaction is carried out in the presence of a basic anion exchange resin, such as Amberlyst A-26, using an excess of epichlorohydrin or epibromohydrin and at an elevated temperature (e.g. about 60 ° C).
• the reaction can be carried out in the presence of an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) and advantageously in the presence of a water-miscible organic solvent (for example a lower alkanol such as methanol or ethanol). in a temperature range from about 0 ° C to about room temperature, preferably at room temperature.
• an alkali metal hydroxide for example sodium hydroxide or potassium hydroxide
• a water-miscible organic solvent for example a lower alkanol such as methanol or ethanol.
• the product obtained from the above reaction is a mixture of an epoxide of the general formula wherein R and R have the above meaning, and the corresponding chlorohydrin or bromohydrin of the general formula wherein R 1 and R 2 are as defined above and X is chlorine or bromine, the chlorohydrin or bromohydrin of the formula IIb normally only occurring in small amounts.
• the 2,3-indoldione derivatives according to the invention (ie compounds of the formula I and their pharmaceutically acceptable acid addition salts) have ⁇ -adrenergic blocking properties. Accordingly, you can fight or prevention of heart diseases, such as angina pectoris and cardiac arrhythmias, can be used. They can also be used as antihypertensive agents.
• the ⁇ -adrenergic blocker properties of the 2,3-indoldione derivatives according to the invention can be demonstrated using standard test methods.
• the beta-adrenergic blocking property in rats is shown by determining that dosage (ED 50 ) of the compound to be tested in ⁇ g / kg iv which is necessary to reduce the isoprenaline-induced tachycardia by 50%.
• the compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments in the form of pharmaceutical preparations which contain them in combination with a compatible pharmaceutical carrier material.
• This carrier material can be an inert organic or inorganic carrier material which is suitable for enteral (eg oral) or parenteral administration. Examples of such carrier materials are water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols, vegetable oils, petroleum jelly and the like.
• the pharmaceutical preparations can be in a solid dosage form (for example as tablets, dragees, suppositories or capsules) or in a liquid dosage form (for example as solutions, suspensions or emulsions).
• the pharmaceutical preparations can be conventional pharmazeu table operations such as sterilization. Furthermore, pharmaceutical preparations can contain conventional auxiliaries, such as preservatives, stabilizers, emulsifiers, flavorings, wetting agents, salts to change the osmotic pressure, buffers, and the like.
• auxiliaries such as preservatives, stabilizers, emulsifiers, flavorings, wetting agents, salts to change the osmotic pressure, buffers, and the like.
• a compound of formula I or a pharmaceutically acceptable acid addition salt thereof can be administered to adults in a daily dose of about 1 mg / kg to 10 mg / kg in a single dose or in multiple doses. It should be noted that the above dosage information is given as examples only, and that the up or down dosages are dependent on factors such as the compound or salt to be administered, the mode of administration and the patient's needs, such as they are determined by the attending doctor, may vary.
• the fractions containing the required product are pooled.
• the product is converted into the oxalic acid salt in isopropanol (5.8 g base require 1.42 g oxalic acid).
• isopropanol / diethyl ether After recrystallization from isopropanol / diethyl ether, 5.28 g of the oxalic acid salt of 1-benzyl-7- (3-t-butylamino-2-hydroxypropoxy) -4-methyl-2,3-indoldione which melts above 220 ° C. is obtained.
• this salt By treating this salt with sodium hydroxide solution in methylene chloride and crystallizing the product obtained from cyclohexane, 2.9 g of the free base of melting point 125-128 ° C. are obtained.
• Tablets containing the following ingredients can be made in a conventional manner:
• Capsules containing the following ingredients can be made in a conventional manner:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Cardiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)

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• 1980
  • 1980-11-26 MC MC801482A patent/MC1357A1/fr unknown
  • 1980-12-01 ZA ZA00807494A patent/ZA807494B/xx unknown
  • 1980-12-01 US US06/211,883 patent/US4395559A/en not_active Expired - Lifetime
  • 1980-12-01 IL IL61603A patent/IL61603A0/xx unknown
  • 1980-12-01 FI FI803727A patent/FI803727L/fi not_active Application Discontinuation
  • 1980-12-01 NZ NZ195702A patent/NZ195702A/en unknown
  • 1980-12-01 AU AU64946/80A patent/AU6494680A/en not_active Abandoned
  • 1980-12-03 HU HU80802878A patent/HU180620B/hu unknown
  • 1980-12-04 AR AR283480A patent/AR226869A1/es active
  • 1980-12-05 JP JP17109080A patent/JPS5695167A/ja active Pending
  • 1980-12-05 NO NO803693A patent/NO803693L/no unknown
  • 1980-12-05 DK DK522180A patent/DK522180A/da unknown
  • 1980-12-05 GR GR63552A patent/GR72136B/el unknown
  • 1980-12-05 EP EP80107669A patent/EP0030380A1/fr not_active Withdrawn
  • 1980-12-05 PT PT72176A patent/PT72176B/pt unknown
  • 1980-12-06 ES ES497530A patent/ES8205770A1/es not_active Expired

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